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hello and welcome to election number 11
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in our ongoing series in drugs and human
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behavior today we are continuing our
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discussions of addiction and the
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processes involved in addiction in
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particular in this lecture we're going
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to focus on the reward pathway and the
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reward pathway is critical to
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understanding addiction why some people
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are more prone to addiction and others
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are not so here's where we are in this
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series in the section on Epidemiology
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and neurobiology of addiction in the
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next lecture we'll actually get into
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more details about how we go from abuse
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to addiction and also talk about how
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epigenetics might be involved in that as
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well so we'll start with the reward
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pathway we'll start off talking about
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the critical role of dopamine this is
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often called the dopamine system or the
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dopamine reward system to provide a
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brief review of the our overview sorry
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of the reward pathways and then finally
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talk about how this all works and
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talking about the functional
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neuroanatomy of the reward system so it
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all starts with dopamine so the reward
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system is one of the major dopamine
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pathways in the brain you have
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significant dopamine productions
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involved in the reward pathway I said
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before it's often referred to as the
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dopamine reward system a couple of key
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areas we're gonna talk about is the
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ventral tegmental area or the VTA the
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nucleus accumbens and the frontal lobes
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the nucleus accumbens is particularly
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important because this is the part of
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the brain which gives us our sense of
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reward in rat studies if you place an
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electrode in this and electrically
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stimulated rats get very addicted to
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that sensation so this is the part
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that's giving us that feeling of reward
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or drugs all reward properties of drugs
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are tied dopamine so traditionally
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dopamine increases in response to
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natural rewards food water sex that sort
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of thing part of our natural rewards and
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we get a nice little dopamine rush
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cocaine
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provides a nice gigantic dopamine rush
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and so is what we call an artificial and
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exaggerated reward so drugs that
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directly increase in a fat dopamine
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levels include nicotine cocaine and
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amphetamines other drugs indirectly
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decrease our increased dopamine by
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inhibiting the effects of gaba on
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dopamine neurons and these include the
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opiates and alcohol so they have the
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rewarding properties indirectly by
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increasing dopamine release whereas
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nicotine cocaine and amphetamine
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directly increase their the amount of
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reward and sorry the amount of dopamine
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thereby directly increasing the feeling
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of reward so next we're going to talk
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about just a general overview of the
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anatomy involved here there are some key
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areas we'll talk about well first talk
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about the role of the hypothalamus in
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sort of natural rewards and consume
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Ettore behaviors well then talk about
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the Me's Olympic pathway and then the
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music cortical pathway and these are two
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important parts of understanding how
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this whole reward system functions let's
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start with the hypothalamus illness is
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critical for a lot of motivated
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behaviors such as eating drinking
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thermoregulation and sex so going out
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finding food water getting cool or
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warming up and also finding sex our
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basic motivational behaviors are part of
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our initial built-in drives epithalamus
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is primarily involved in consumed Ettore
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behaviors not goal directed behaviors
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and that's an important distinction
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because oftentimes drug rewards are far
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more involved and these sort of goal
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directed behavior is going on finding
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drugs getting that reward etc we do know
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that activation of the
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hypothalamic-pituitary-adrenal axis
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during times of stress can trigger needs
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for reward and that's something that's
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very important to understand is stress
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can oftentimes be a trigger for drug use
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and drug abuse episodes particularly for
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people who are trying to recover as ADD
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stressful situations can push them back
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into drug use and so it's very important
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to keep an eye on friends that you might
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know who might be vulnerable to this
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kind of problem so that gets us then to
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the Meisel limbic dopamine pathway
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primarily involved in the limbic system
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involving the ventral tegmental area the
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nucleus accumbens a little bit of the
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amygdala so if we look here we have the
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ventral tegmental area here at the top
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of the brain stem and the tectum the
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medium forebrain bundle and then the
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nucleus accumbens and then the rest of
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the limbic system including the
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hypothetic AMPAS the amygdala etc we'll
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start with the ventral tegmental area
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it's on the midline floor of the
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midbrain it receives input from the
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subcortical attention system that's an
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important part of understanding how
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attention related cues might be related
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to rewards so oftentimes drug-related
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cues can direct people attention more
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towards the idea of drug consumption the
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nucleus accumbens the medium forebrain
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bundle somehow these got out of order as
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a bundle of dopaminergic neurons which
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connects the ventral tegmental area to
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the nucleus accumbens in the limbic
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system and so this is a connection
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between the VTA the nucleus accumbens
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and the limbic system limbic system is
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going to be involved in memory for drug
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rewards learning about drugs learning
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about rewards how we go out and find
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rewards again remembering drug abuse
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episodes and the nucleus accumbens of
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course is going to be involved primarily
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in our feelings of reward this is part
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of the ventral striatum this is where
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all of our feelings of reward are
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generated and so on we're ratcheting up
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the nucleus accumbens we're getting
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larger and larger feelings of reward and
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in the limbic system the medial
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forebrain bundle projects to the
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olfactory tubercle rates the septum the
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amygdala and the hippocampus
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mickeleh is of course involved in our
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emotional responses and the hippocampus
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is involved in memory learning etc and
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so it also has important roles in
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top-down regulation of the HPA axis so
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anything that might damage the
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hippocampus can actually alter our
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responses to stress and so when we start
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talking about through the role of stress
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in drug abuse this becomes an important
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part of that it gets us to the muse of
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cortical pathway it starts at the
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ventral tegmental area and then travels
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upward to the prefrontal areas the
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cingulate and the paranal cortex these
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important things include motor
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functioning compulsion / separation in
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the frontal cortex our ability to assess
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risk is particularly important in fact
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we know drugs like cocaine and
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amphetamines alter our perception of
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risk and so that's one of the important
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behavioral aspects of these particular
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drugs we also know and it's important to
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note we'll talk a little bit more about
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this here in a moment
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that the frontal lobes are involved in
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what's called working memory and working
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memory is our ability to manipulate and
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work with information but also to
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actively inhibit information and so
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people with strong working memory can
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inhibit things like drug cues and so
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what we see is that people with high
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levels of working memory or at less risk
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for drug addiction while they may still
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use drugs they are often what we call
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weekend warriors who are able to resist
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the urge to do drugs while they have
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other things to do then they go out on
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the weekends party it up and then go
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back to work on Monday it's that high
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level of working memory that allows them
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to do that now the open question is the
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longer they do that will they still have
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that high level of working memory and
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that's an important thing to consider so
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we'll talk then about how this works we
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call the functional anatomy of the
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reward pathways we'll talk first about
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the reward prediction error signal then
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incentive salience reward euphoria and
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then anticipation of reward and have it
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formation work with start with the
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reward prediction error signal initially
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dopamine neurons in the ventral
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tegmental area respond to the presence
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of a reward so these neurons only
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respond when the reward is given if a
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sensory cue predicts that reward those
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dopamine neurons fire in response to the
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cue not the reward now if we go back to
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first principles remember how in basic
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operant conditioning in conditioned an
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animal to respond to a cue rather than
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the reward itself this is the entire
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basis of clicker training with dogs
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that clicker is associated with the
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treat reward and so that clicker is
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actually providing the same sense of
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reward in the brain that's why clicker
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training works is because of that
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however if a reward fails to occur those
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dopamine neurons will decrease their
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firing and so you do have to
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occasionally pair that clicker with
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treats as well we also know is that an
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unexpected reward results in a higher
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dopamine release in greater learning now
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the sort of functional part of this is
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if you find an unexpected source of food
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water sex it's important that you
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remember that because that's an
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important survival aspect when you're
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trying to learn how to find food water
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and sex is what are the things that
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result result in that now comes to drugs
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unexpected drug use unexpected rewards
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can result in greater learning and so
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often times they're over-represented in
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sort of our learning pans so this is how
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we start to associate cues with reward
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and again in drug abuse we do know that
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certain cues are associated with
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triggering drug abuse episodes and in
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fact oftentimes in research settings we
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use cues to see how people are
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responding to things like medication and
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so a drug related cue might be for
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someone who uses cocaine you might show
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them a picture of a pile of cocaine the
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stuff you would use to snort cocaine a
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straw or
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bill or whatever people are using and so
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those cues then get associated with that
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reward and then reinforce that behavior
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further sense of salience occurs the
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mesolimbic pathway enhances the
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motivational properties of cues are
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predictive of rewards so we're more
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motivated to go out and find those
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rewards and so that's why it's called
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incentives aliens because we're
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incentivized to go out and find those
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rewards and also we are more likely to
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pay attention and those cues become more
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salient so that motivation is associated
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with activation of the amygdala are
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pretty again is referred to as incentive
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salience these motivational states then
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increase the incentive salience of
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reward and related cues that is we are
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more likely to be able to find them
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we're more incentivized to go out and
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find them
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for that reward and cues that are
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associated with it and so this is an
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important part of again how we try to
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figure out how to find food water etc
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that also can be associated with
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motivational states that increase the
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salience of reward and related cues so
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if somebody's trying to find drugs they
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may be able to focus more closely on
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people's behavior trying to see if
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somebody else is doing drugs etc reward
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you work for you then this is where the
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high from our reward comes from this
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comes from the nucleus accumbens most
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research in this area involves cocaine
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and amphetamines because they both cause
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substantial increases in synaptic
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dopamine blockades of dopamine in the
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nucleus accumbens decrease the
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reinforcing effects of rewards in
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animals I do want to say for just one
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moment and this may actually be later on
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in the lecture but I would be remiss to
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not say it now one of my criticisms of
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research in the reward pathway about
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things that aren't drugs candy crush if
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people get addicted to video games they
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all say Facebook's just like cocaine
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it's not and I think that's really
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important yes it involves the same brain
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areas but it is not the same as go
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and I think that's an important thing to
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keep a bio dive it gets us then to
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anticipation of reward and habit
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formation there are reciprocal
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connections from the prefrontal cortex
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and the hippocampus that drive
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anticipation and craving and so we're
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able to control those cravings or
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anticipate drug use based on these
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connections from the frontal lobe as I
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was saying earlier reductions in
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executive functions such as working
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memory can contribute to the incentive
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salience of drugs and other artificial
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rewards over natural rewards and what
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that means is that if our working memory
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capacity is reduced and we are more
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likely to focus on artificial rewards
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rather than natural rewards now what is
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our executive functions get reduced
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primarily through stress in particular
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high-stress situations caused the
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release of cortisol cortisol reduces our
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executive functioning and that stress
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then can lead us to seek out artificial
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rewards over natural rewards and so
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stress you're going to see throughout
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the semester is a really critical part
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of mental illness in particular drug use
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and depression
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all these reciprocal connections from
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the frontal lobe have exert both
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top-down and bottom-up influences on
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this entire pathway and our important
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part of our ability to control things
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like when and then with some quick
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discussions about our differential
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vulnerability to addiction the first
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critical thing to understand is stress
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is an important factor when it comes to
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drug drug use drug abuse in a particular
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drug addiction because people who are
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under high levels of stress chronic
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stress are at much greater risk for
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they're much more likely to seek out
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artificial rewards over natural rewards
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because that stress has reduced their
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working memory capacity or their
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executive function so it's a critical
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part of understanding how people end up
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abusing drugs is because of stress and
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it's one of the things I mentioned in
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the previous lecture that we are facing
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an opioid crisis that of course has a
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lot to do with the availability of these
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drugs but also has to do with the nature
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of our society I think we all can agree
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that things are much more stressful than
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they used to be and I think that's
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something we need to be mindful of
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social context this is another really
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important part of understanding
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addiction in particular social support
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in particular for people under stress so
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in the early research on cocaine with
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rats they used rats that were kept in
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cages brought them out of them to have
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gave them access to cocaine water they
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were very motivated to get to that
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cocaine water every time they went back
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to it but rats are not solitary
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creatures much like people are not
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solitary creatures and so in later
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research if the rats were in a colony
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with lots of other rats to hang out with
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they went back to the cocaine water on
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occasion but not chronically or in
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addictive fashion as social context
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blunted the need for that drug because
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they weren't as stressed out
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finally genetics and epigenetics and
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this is an area of emerging interest
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probably the clearest area that we can
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see this in is in nicotine addiction
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there appears to be one particular
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genotype and what we call harden smokers
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for people that are much more nicotine
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than others and so how people respond to
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a particular drug probably also has a
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thing to do with their genetics let's
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talk more about epigenetics in the next
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lecture but we do know based on animal
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research that drugs can change genetic
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expression in an individual and that can
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be passed down to subsequent generations
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what's interesting about that in a study
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on cocaine in rats they discovered that
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if you gave cocaine to a rat its
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grandchildren liked cocaine less
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compared to other rats and so they were
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actually less likely to use cocaine than
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rats who did not have that epigenetic
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alteration what that alteration is is
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not particularly clear but particularly
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interesting all right well that gets us
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to the end of the reward pathway I'll
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become that interesting we will pick up
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next with from abuse to addiction
